(a) Technical Field
The present invention relates to 6-pyrazolylamido-3-substituted azabicyclo[3.1.0]hexane derivatives useful as calcium channel inhibitors, pharmaceutically acceptable salts thereof and a medical use of the calcium channel inhibiting effect of the compounds for treatment of diseases.
(b) Background Art
Voltage-gated calcium channels play important roles in various intracellular signal transductions by increasing the concentration of calcium ions in response to stimuli to neurons. The calcium channels are divided into high-voltage activated calcium channels and low-voltage activated calcium channels. A representative low-voltage activated calcium channel is the T-type calcium channel.
The T-type calcium channels are found in the central nervous system, adrenal glands, sinoatrial node of the heart, or the like. T-type calcium channel blockers are known to be effective in treatment of cerebral diseases and cardiac diseases such as epilepsy, hypertension, angina, etc. [1) Hosravani, Houman et al., “Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy”, Annals of Neurology (2005), 57 (5), 745-749; 2) Vitko, Iuliia et al., “Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel”, Journal of Neuroscience (2005), 25 (19), 4844-4855; 3) Clozel, Cardiovas Drugs Ther. (1990), 4, pp. 731-736; 4) Hefti, Arzneimittelforschung (1990), 40, 417-421; 5) Moosmang, Sven et al., “Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Cav1.2”, Circulation Research (2006), 98 (1), 105-110].
It is also reported that the T-type calcium channels are involved in the proliferation of cancer cells and T-type calcium channel blockers are effective anticancer agents that inhibit the proliferation of cancer cells [Functional role of T-type calcium channel in tumor growth and progression: prospective in cancer therapy” British Journal of Pharmacology, (2012), 166, 1244-1246]
Recent reports have revealed that T-type calcium channel blockers have therapeutic effects on pain. For example, the T-type calcium channel blockers mibefradil and ethosuximide were shown to inhibit mechanically and thermally induced pain in a dose-dependent manner in a spinal nerve ligation model, indicating that T-type calcium channel blockers are useful in the treatment of neuropathic pain [Dogrul, Ahmet et al., “Reversal of experimental neuropathic pain by T-type calcium channel blockers”, Pain, 2003, 105, 159-168].
Some drugs having calcium channel inhibition activity have been approved as pharmaceutical drugs. Gabapentin (Neurontin™) and ziconotide (Prialt™) were approved by the FDA as anticonvulsant and for treatment of neuropathic pain but there are problems of limited application depending on patients and tranquilizing effect caused by overdosage. Especially the T-type calcium channel inhibitor Mibefradil (Ro 40-5967, WO 98/49149) had been used to treat hypertension and angina. However, it is metabolized by cytochrome P-450 3A4 and 2D6 and interacts with other drugs pharmacokinetically, thereby resulting in various side effects. As a result, mibefradil has been withdrawn from the market and there is no drug that can be used as a T-type calcium channel blocker. Accordingly, development of a new T-type calcium channel blocker is urgently needed.
The inventors of the present invention have made efforts to develop novel compounds that act on calcium channels. As a result, they have found out that 6-pyrazolylamido-3-substituted azabicyclo[3.1.0]hexane derivatives synthesized as novel compounds have superior antagonistic activity against T-type calcium channels.